Process for production cilostazol

ABSTRACT

The present invention provides a process for producing cilostazol [I] in a high yield and a high purity, by reacting a carbostyril derivative [II] with a tetrazole derivative [III] in the presence of an inorganic basic compound in a solvent of water, wherein water is used in an amount of 3 to 7-fold weight to that of the carbostyril derivative [II] and the inorganic basic compound is used in an amount of 1 to 6 mol per mol of the carbostyril derivative [II]. The process of the present invention is the improved and environment-friendly process for producing cilostazol being useful for pharmaceuticals

TECHNICAL FIELD

The present invention relates to a novel process for producingcilostazol represented by the following formula [I]:

BACKGROUND ART

Cilostazol, prepared according to the present invention, whose chemicalname is6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydrocarbostyril, isknown to be useful as an antithrombotic agent, a cerebral circulationimprover, an anti-inflammatory agent, an antiulcer agent, a hypotensiveagent, an antiasthmatic agent, and a phosphodiesterase inhibitor, etc.(see e.g. JP-A-56-49378).

As for the process for producing cilostazol, it is known a processcomprising a reaction of a carbostyril derivative represented by thefollowing general formula [II]:

with a tetrazole derivative represented by the following general formula[III]:

(wherein X represents a halogen atom), in the presence of an inorganicbase or an organic base (see e.g. JP-A-56-49378 and Chem. Pharm. Bull.,31(4), 1151–1157 (1983)).

According to the above-mentioned known process, the yield of cilostazolis as low as about 50 to 74%, because there is also formed a compound inwhich the tetrazole derivative of general formula [III] has reacted notonly with the hydroxyl group of the carbostyril derivative of generalformula [II] but also with the 1-position of the cilostazol [I]simultaneously. The thus formed contaminative impurity, i.e. thecompound in which the 1-position of the cilostazol [I] is substituted bythe tetrazole derivative of general formula [III], is difficult toremove. Accordingly, there is a disadvantage of the known process thatthe production of the cilostazol with a high purity has required acomplicated process of purification.

Another process for producing cilostazol, it is known a processcomprising a reaction of the above-mentioned carbostyril derivative ofthe formula [II] with the above-mentioned tetrazole derivative of theformula [III], in the presence of a phase transfer catalyst (see e.g.JP-A-2001-213877 and WO 02/14283).

Yet another process for producing cilostazol, it is proposed a processcomprising a reaction of the above-mentioned carbostyril derivative ofthe formula [II] with the above-mentioned tetrazole derivative of theformula [III], in a non-aqueous hydroxylic solvent in the presence oftwo kinds of basic compound or in a non-aqueous solvent in the presenceof molecular sieves to scavenge water formed as a byproduct (see e.g. WO02/14283).

However, these known processes inevitably use undesirable materials suchas organic solvents and reagents in view of environmental hygiene. Onthe basis of the growing conscious to international environmentalconservation in recent years, great demands become arisen in a chemicalindustry to make every effort decreasing use of the solvents andreagents pointed out the harmfulness, and preventing those materialsfrom discharging into the environment. In order to fulfil those demands,established processes have to be down for a consideration, alternativeraw materials, reagents and solvents being less harmful have to be foundout, and the processes having higher conversion rate, yield andselectivity have to be developed; so that the environmental load can bediminished.

Under the circumstances with these social demands, the present inventorshave made a study of the process being safer for the environment, forproducing cilostazol with using water as a solvent in place of anorganic solvent. Heretofore, the chemical reaction has been consideredto be efficiently proceeding in the system wherein the reactivesubstances are dissolved. On the study of the process for producingcilostazol so far, water has never been used as a solvent, since thetetrazole derivative of the formula [III] is absolutely insoluble inwater and the tetrazole derivative of the formula [III] is expected tobe decomposed in water.

On the other hand, in view of the above-mentioned demands for theenvironmental hygiene, the present inventors have conducted furtherstudies with the aim of establishing the process using water as asolvent by all means. As a result, the present inventors have found thatthe objective process is established by applying the specificconditions, and thereby the objects of the present invention can beachieved. Based on this finding, the present invention has beenaccomplished.

DISCLOSURE OF THE INVENTION

According to the studies made by the present inventors, it has beenfound that, by using water as a solvent in an amount of 3 to 7-foldweight to that of carbostyril derivative of the formula [II] and byusing inorganic basic compounds in an amount of 1 to 6 molar quantityper mol of carbostyril derivative of the formula [II], the reaction forproducing cilostazol may proceed without decomposition of the tetrazolederivative of the general formula [III], and besides the formation ofthe compound in which the 1-position of cilostazol is substituted by thetetrazole derivative of general formula [III] may be suppressed.

That is, the object of the present invention is to provide an improvedprocess for producing the objective cilostazol with high yield andpurity, by the reaction of the carbostyril derivative of the formula[II] with the tetrazole derivative of the formula [III], in water as asolvent at the amount of 3 to 7-fold weight to that of carbostyrilderivative of the formula [II], in the presence of inorganic basiccompounds at the amount of 1 to 6 molar quantity per mol of carbostyrilderivative of the formula [II].

Accordingly, it is the object of the present invention to provide aprocess for producing cilostazol, as a process being safe forenvironment. It is another object of the present invention to provide aprocess for producing cilostazol at a low cost and by a simpleprocedure. It is yet another object of the present invention to providea process for producing cilostazol without any complicated process ofpurification, in a high yield, and in a high purity. It is yet anotherobject of the present invention to provide an industrially advantageousprocess for producing cilostazol.

According to the process of the present invention, by usingenvironment-friendly water as a solvent, the objective cilostazol can beproduced on an industrial scale, at a low cost, by a simple procedure,in a high yield and in a high purity. Thus, the process of the presentinvention is of great worth as a process for producing cilostazol beinguseful for pharmaceuticals industrially.

BEST MODE FOR CARRYING OUT THE INVENTION

The improved process for producing cilostazol of the present inventionis further explained in detail below.

The process of the present invention is indicated as the followingreaction scheme-1.

(wherein X is a halogen atom selected from the group consisting of afluorine atom, a chlorine atom, a bromine atom and an iodine atom, amongwhich particularly preferred is a chlorine atom).

In the reaction scheme-1the reaction between a carbostyril derivative ofthe formula [II] and a tetrazole derivative of the general formula [III]is carried out in water at the amount of 3 to 7-fold weight to that ofcarbostyril derivative of the formula [II], in the presence of inorganicbasic compounds at the amount of 1 to 6 molar quantity per mol ofcarbostyril derivative of the formula [II].

As the inorganic basic compound, known ones can be used extensively.Examples thereof include inorganic bases such as sodium hydroxide,potassium hydroxide, cesium hydroxide, lithium hydroxide, sodiumcarbonate, potassium carbonate, cesium carbonate, lithium carbonate,lithium hydrogen carbonate, sodium hydrogen carbonate, potassiumhydrogen carbonate, silver carbonate and the like; alkali metals such assodium, potassium and the like; and mixtures thereof. In case of usingone kind of inorganic basic compound alone, any one of the alkalinemetal carbonates selected from the group consisting of sodium carbonate,potassium carbonate, cesium carbonate, lithium carbonate, lithiumhydrogen carbonate, sodium hydrogen carbonate, potassium hydrogencarbonate and the like is particularly preferred, and the preferableamount thereof is 1 to 6 mol per mol of the carbostyril derivative [II],particularly preferable 1 to 5 mol per mol of the carbostyril derivative[II]. In case of using two or more kinds of inorganic basic compound bymixture, a mixture of one or two or more alkaline metal hydroxidesselected from the group consisting of sodium hydroxide, potassiumhydroxide, cesium hydroxide, lithium hydroxide and the like; and one ortwo or more alkaline metal hydroxides selected from the group consistingof sodium carbonate, potassium carbonate, cesium carbonate, lithiumcarbonate, lithium hydrogen carbonate, sodium hydrogen carbonate,potassium hydrogen carbonate and the like is particularly preferred. Incase of using the mixture, the amount of the alkaline metal hydroxide tobe used is 0.4 to 1 mol, preferably 0.4 to 0.9 mol per mol of thecarbostyril derivative [II], and the amount of the alkaline metalcarbonate to be used is 1 to 5 mol, preferably 2 to 5 mol per mol of thecarbostyril derivative [II]. When using the mixture, the total amount ofthe inorganic basic compounds is usually 1 to 6 mol, preferably 1 to 5mol per mol of the carbostyril derivative [II].

The reaction is carried out usually at a temperature not lower thanambient temperature and not higher than 200° C., and preferably at atemperature of 50 to 150° C. The reaction time is usually from about onehour to about 20 hours. It is recommended to use the tetrazolederivative [III] usually in an amount of at least 0.5 mol, preferably0.5 to 1.5 mol, and more preferably 1.1 to 1.5 mol per mol of thecarbostyril derivative [II].

In the above-mentioned reaction, a lower alcohol may be added to thereaction system in a certain amount thereof which does not affectenvironment. For example, a lower alcohol such as methanol, ethanol,propanol, isopropyl alcohol, butanol, ethylene glycol or the like may beadded in an amount of 5 to 30% by volume to the amount of water.Further, sodium sulfite, sodium thiosulfate or the like may be added tothe reaction system of the above-mentioned reaction for the purpose ofpreventing the coloration caused by oxidation.

The reaction may be carried out with circulating the reaction mixture bycontinuous disperser. The reaction mixture is repeatedly introduced intothe continuous disperser and pulverized therein, then returned to thereaction vessel so as to circulate the reaction mixture constantly. Thecirculation of the reaction mixture can prevent the crystals of theobjective product of cilostazol from adhering with each other to makebig agglomerates.

Cilostazol of the formula [I] obtained by the above-mentioned reactioncan be easily isolated by the conventional separating means. As saidseparating means, mention can be made of, for example, method comprisingcooling the reaction mixture, followed by collecting the crystals byfiltration; method comprising heating the crystals and washing it withalcohol such methanol or the like, followed by distilling off thesolvent and cooling so as to obtain the crystals; extraction methodusing a solvent; dilution method; recrystallization method; columnchromatography; preparative thin layer chromatography; etc.

EXAMPLES

Next, the process of the present invention is more specificallyexplained below with reference to examples.

The purity of the products obtained in the examples was determined byhigh performance liquid chromatography (HPLC) under the followingconditions.

-   -   Detector: Ultraviolet rays absorptiometer    -   Column: equivalent of YMC-pack SIL 120A    -   Eluent: CH₂Cl₂:n-hexane:MeOH=20:10:1    -   Flow rate: about 1.0 ml/min.    -   Wavelength detected: 254 nm

Example 1

Into a reaction vessel having a capacity of 500 mL were introduced6-hydroxy-3,4-dihydrocarbostyril (30 g, 0.18 mol),1-cyclohexyl-5-(4-chlorobutyl)-1,2,3,4-tetrazole (49.09 g, 0.20 mol, 1.1M), potassium carbonate (55.90 g, 0.40 mol, 2.2 M), sodium hydroxide(5.88 g, 0.15 mol, 0.8 M), sodium sulfite (1.5 g, 0.01 mol) and purifiedwater (150 ml). The mixture of the reactants was heated at about 92° C.for about 6 hours with circulating by continuous disperser (pipelinehomomixer T.K.ROBO MIX manufactured by TOKUSHUKIKA KOGYO CO. LTD.).After the completion of the reaction, the reaction mixture was cooled toaround 50° C., and the mixture was introduced into a flask having acapacity of 1 L, methanol (150 mL) was added thereto and the resultingreaction mixture was refluxed with heating for about 2 hours. Themixture was cooled to the ambient temperature and the precipitatedcrystalline product was collected by filtration and washed with purifiedwater (150 mL), methanol (90 mL), followed by purified water (150 mL),then dried at about 80° C. Thus, 62.14 g of cilostazol was obtained.Yield: 91.48%, Purity: 99.66%, m.p.: 158–159° C.

Example 2

Into a flask having a capacity of 200 mL were introduced6-hydroxy-3,4-dihydrocarbostyril (12 g, 0.07 mol),1-cyclohexyl-5-(4-chlorobutyl)-1,2,3,4-tetrazole (19.64 g, 0.08 mol),potassium carbonate (22.36 g, 0.16 mol), sodium hydroxide (2.35 g, 0.05mol), sodium sulfite (0.6 g, 0.004 mol) and purified water (60 mL). Themixture of the reactants was heated at about 92° C. for about 6 hours.After the completion of the reaction, the reaction mixture was cooled toaround 50° C., and the deposited crude crystals were once collected byfiltration. The crystals obtained were introduced into a flask andpurified water (120 mL) was added thereto, then the crystals were washedwith stirring at about 85° C. for about 15 minutes. The reaction mixturewas cooled to around 50° C., and the precipitated crystals werecollected by filtration. The crystals obtained were introduced into aflask again and methanol (84 mL) was added thereto, then the crystalswere washed with stirring at about 25° C. for about 15 minutes. Thereaction mixture was cooled to 10° C. or less, the precipitatedcrystalline product was collected by filtration and washed with methanol(24 mL), then dried at about 80° C. Thus, 24.15 g of cilostazol wasobtained. Yield: 88.88%, Purity: 99.50%, m.p.: 158–159° C.

Example 3

Into a reaction vessel having a capacity of 500 mL were introduced6-hydroxy-3,4-dihydrocarbostyril (30 g, 0.18 mol),1-cyclohexyl-5-(4-chlorobutyl)-1,2,3,4-tetrazole (49.1 g, 0.20 mol, 1.1M), potassium carbonate (83.84 g, 0.61 mol, 3.3 M), sodium sulfite (1.5g, 0.01 mol) and purified water (150 mL). The mixture of the reactantswas heated at about 85° C. for about 6 hours with circulating bycontinuous disperser (pipeline homomixer T.K.ROBO MIX manufactured byTOKUSHUKIKA KOGYO CO. LTD.). After the completion of the reaction, thereaction mixture was cooled to around 50° C. and the deposited crudecrystals were once collected by filtration. The crystals obtained wereintroduced into a flask having a capacity of 1 L and purified water (300mL) was added thereto, then the crystals were washed with stirring atabout 85° C. for about 15 minutes. After washing the crystals, thereaction mixture was cooled to around 50° C. and the precipitatedcrystals were collected by filtration. The crystals obtained wereintroduced into a flask again and methanol (210 mL) was added thereto,then the crystals were washed with stirring at about 25° C. for about 15minutes. The reaction mixture was cooled to 10° C. or less, theprecipitated crystalline product was collected by filtration and washedwith methanol (60 mL), then dried at about 80° C. Thus, 62.79 g ofcilostazol was obtained. Yield: 92.44%, Purity: 99.61%, m.p.: 158–159°C.

Example 4

Into a flask having-a capacity of 200 ml were introduced6-hydroxy-3,4-dihydrocarbostyril (12 g, 0.07 mol),1-cyclohexyl-5-(4-chlorobutyl)-1,2,3,4-tetrazole (19.64 g, 0.08 mol, 1.1M), potassium carbonate (33.54 g, 0.24 mol, 3.3 M), sodium sulfite (0.6g, 0.004 mol) and purified water (60 mL). The mixture of the reactantswas heated at about 85° C. for 6 hours. After the completion of thereaction, the reaction mixture was cooled to around 50° C., and theprecipitated crystals were collected by filtration. The crystalsobtained were introduced into a flask, and purified water (120 mL) wasadded thereto, then the crystals were washed with stirring at about 85°C. for about 15 minutes. After washing the crystals, the reactionmixture was cooled to around 50° C. and the precipitated crystals werecollected by filtration. The crystals obtained were introduced into aflask again and methanol (84 mL) was added thereto, and the crystalswere washed with stirring at about 25° C. for about 15 minutes. Thereaction mixture was cooled to 10° C. or less, the precipitatedcrystalline product was collected by filtration and washed with methanol(24 mL), then dried at about 80° C. Thus, 24.28 g of cilostazol wasobtained. Yield: 89.36%, Purity: 99.44%, m.p.: 158–159° C.

Example 5

Into a flask having a capacity of 200 ml were introduced6-hydroxy-3,4-dihydrocarbostyril (12 g, 0.07 mol),1-cyclohexyl-5-(4-chlorobutyl)-1,2,3,4-tetrazole (19.64 g, 0.08 mol),potassium carbonate (22.36 g, 0.16 mol), sodium hydroxide (2.35 g, 0.05mol), sodium sulfite (0.6 g, 0.004 mol), purified water (36 mL) andisopropanol (3.6 mL), and the reaction was conducted for about 6 hoursunder reflux. After the completion of the reaction, the reaction mixturewas cooled to around 10° C., and the precipitated crystals werecollected by filtration. The crystals obtained were introduced into aflask, and purified water (120 mL) was added thereto, then the crystalswere washed with stirring at about 85° C. for about 15 minutes. Thereaction mixture was cooled to around 50° C. and the precipitatedcrystals were collected by filtration. The crystals obtained wereintroduced into a flask again and methanol (84 mL) was added thereto,then the crystals were washed with stirring at about 25° C. for about 15minutes. The reaction mixture was cooled to 10° C. or less, theprecipitated crystalline product was collected by filtration and washedwith methanol (24 mL), then dried at about 80° C. Thus, 24.31 g ofcilostazol was obtained. Yield: 89.47%, Purity: 99.45%, m.p.: 158–159°C.

1. A process for producing cilostazol represented by the followinggeneral formula [I]:

which comprises reacting a carbostyril derivative represented by thefollowing general formula (II):

with a tetrazole derivative represented by the following general formula(III):

(wherein X represents a halogen atom), in the presence of an inorganicbasic compound in a solvent of water, wherein water is used in an amountof 3 to 7-fold weight to that of the carbostyril derivative [II] and theinorganic basic compound is used in an amount of 1 to 6 mol per mol ofthe carbostyril derivative [II].
 2. The process according to claim 1,wherein said inorganic basic compound is selected from the groupconsisting of inorganic bases of sodium hydroxide, potassium hydroxide,cesium hydroxide, lithium hydroxide, sodium carbonate, potassiumcarbonate, cesium carbonate, lithium carbonate, lithium hydrogencarbonate, sodium hydrogen carbonate, potassium hydrogen carbonate andsilver carbonate; alkali metals of sodium and potassium; and mixturesthereof.
 3. The process according to claim 2, wherein said inorganicbasic compound is one kind of alkaline metal carbonate selected from thegroup consisting of sodium carbonate, potassium carbonate, cesiumcarbonate, lithium carbonate, lithium hydrogen carbonate, sodiumhydrogen carbonate and potassium hydrogen carbonate.
 4. The processaccording to claim 2, wherein said inorganic basic compound is a mixtureof one or two or more alkaline metal hydroxides selected from the groupconsisting of sodium hydroxide, potassium hydroxide, cesium hydroxideand lithium hydroxide; and one or two or more alkaline metal carbonatesselected from the group consisting of sodium carbonate, potassiumcarbonate, cesium carbonate, lithium carbonate, lithium hydrogencarbonate, sodium hydrogen carbonate and potassium hydrogen carbonate.5. The process according to claim 4, wherein the amount of said alkalinemetal hydroxides to be used is 0.4 to 1 mol per mol of the carbostyrilderivative [II], and the amount of said alkaline metal carbonates to beused is 1 to 5 mol per mol of the carbostyril derivative [II].
 6. Theprocess according to claim 1, wherein the amount of the tetrazolederivative [III] to be used is at least 0.5 mol per mol of thecarbostyril derivative [II].
 7. The process according to claim 1,wherein X is a chlorine atom.